Genetic Variant NM_006129.5:c.6C>T (chr8-22165411-C-T) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP7

The NM_006129.5(BMP1):c.6C>T(p.Pro2Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000736 in 1,358,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P2P) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.4e-7 ( 0 hom. )

Consequence

BMP1
NM_006129.5 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.593

Publications

0 publications found

Variant links:

Genes affected

BMP1 (HGNC:1067): (bone morphogenetic protein 1) This gene encodes a protein that is capable of inducing formation of cartilage in vivo. Although other bone morphogenetic proteins are members of the TGF-beta superfamily, this gene encodes a protein that is not closely related to other known growth factors. This gene is expressed as alternatively spliced variants that share an N-terminal protease domain but differ in their C-terminal region. [provided by RefSeq, Aug 2008]

BMP1 Gene-Disease associations (from GenCC):

osteogenesis imperfecta type 13
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
high bone mass osteogenesis imperfecta
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
osteogenesis imperfecta type 3
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

BMP1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.2).

BP7

Synonymous conserved (PhyloP=0.593 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006129.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BMP1	NM_006129.5	MANE Select	c.6C>T	p.Pro2Pro	synonymous	Exon 1 of 20	NP_006120.1	P13497-1
BMP1	NM_001199.4	MANE Plus Clinical	c.6C>T	p.Pro2Pro	synonymous	Exon 1 of 16	NP_001190.1	P13497-2
BMP1	NR_033403.2		n.40C>T		non_coding_transcript_exon	Exon 1 of 20

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BMP1	ENST00000306385.10	TSL:1 MANE Select	c.6C>T	p.Pro2Pro	synonymous	Exon 1 of 20	ENSP00000305714.5	P13497-1
BMP1	ENST00000306349.13	TSL:1 MANE Plus Clinical	c.6C>T	p.Pro2Pro	synonymous	Exon 1 of 16	ENSP00000306121.8	P13497-2
BMP1	ENST00000471755.5	TSL:1	n.6C>T		non_coding_transcript_exon	Exon 1 of 16	ENSP00000428665.1	P13497-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.36e-7

AC:

AN:

1358784

Hom.:

Cov.:

AF XY:

0.00000149

AC XY:

AN XY:

672590

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

27528

American (AMR)

AF:

0.00

AC:

AN:

25598

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22750

East Asian (EAS)

AF:

0.00

AC:

AN:

31444

South Asian (SAS)

AF:

0.00

AC:

AN:

73652

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48368

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5170

European-Non Finnish (NFE)

AF:

9.36e-7

AC:

AN:

1068436

Other (OTH)

AF:

0.00

AC:

AN:

55838

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.20

CADD

Benign

(source)

DANN

Benign

0.97

PhyloP100

0.59

PromoterAI

-0.0040

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over